Inflammation initiates ___ process may injure normal tissues too strong of a response ( ___ infection) prolonged response ( ___ infection) inappropriate response ( ___-antigens, ___ disease) 5 signs

healing severe persistent/recurrent self-antigens, autoimmune heat (calor), redness (rubor), swelling (tumor), pain (dolor), loss of function (functio laesa)

Chemical mediators of inflammation vasoactive ___ (histamine and ___ ) Eicosanoids (prostaglandins, ___, and lipoxins) ___ activating factor (PAF) Cytokines (TNF, IL-___, chemokines → ___ inflammation) (IFN-y → ___ inflammation) complement components (C3a and C5a) Coagulation and kinin systems (bradykin, thrombin, fibrinopeptides)

amines, serotonin leukotrienes platelet 1, acute chronic

Eicosanoids ___-lived mediators (seconds to minutes) ___ and paracrine signaling bind GPCRs in target cells (Gs and Gq) Gs = ___ Gq = ___

short autocrine dilation constriction

NSAIDs - 20,21 Flashcards by Reagan Smith

Inflammation

initiates ___ process
may injure normal tissues
too strong of a response ( ___ infection)
prolonged response ( ___ infection)
inappropriate response ( ___-antigens, ___ disease)
5 signs

healing
severe
persistent/recurrent
self-antigens, autoimmune
heat (calor), redness (rubor), swelling (tumor), pain (dolor), loss of function (functio laesa)

How well did you know this?

Not at all

Perfectly

Chemical mediators of inflammation

vasoactive ___ (histamine and ___ )
Eicosanoids (prostaglandins, ___, and lipoxins)
___ activating factor (PAF)
Cytokines (TNF, IL-___, chemokines → ___ inflammation) (IFN-y → ___ inflammation)
complement components (C3a and C5a)
Coagulation and kinin systems (bradykin, thrombin, fibrinopeptides)

amines, serotonin
leukotrienes
platelet
1, acute
chronic

How well did you know this?

Not at all

Perfectly

What is this?

PAF

How well did you know this?

Not at all

Perfectly

T or F: Eicosa means 30

False; 20, eicosanoids will have 20 or more carbons

How well did you know this?

Not at all

Perfectly

Eicosanoids

4 types
PGE2- Blood vessel ___ , brochi ___ , uterus ___
PGF2a - blood vessels ___ , bronchi ___ , uterus ___
PGI2 - blood vessels ___ , platelets ___
TXA2 - blood vessles ___ , platelets ___

dilation, dilation oxytocic dilation
constriction, contriction, oxytocic constriction
dialtion, inhibits aggregation
constriction, aggregation (clotting)

How well did you know this?

Not at all

Perfectly

prostaglandin = ___
leukotrienes = ___
lipoxin = ___

inflammation
allergies
anti-inflammatory

How well did you know this?

Not at all

Perfectly

Eicosanoids

___-lived mediators (seconds to minutes)
___ and paracrine signaling
bind GPCRs in target cells (Gs and Gq)
Gs = ___
Gq = ___

short
autocrine
dilation
constriction

How well did you know this?

Not at all

Perfectly

Arachidonic acid

20-carbon polyunsaturated fatty acids
___ fatty acids
most abundant and important ___ of eicosanoids
Released from membrane phospholipids by ___ (PLA2)
corticosteroids ___ the production of phospholipase A2

essential
precursor
phospholipase A2
suppress

How well did you know this?

Not at all

Perfectly

Oxygenation of arachidonic acid

PGH synthase ( ___ ) pathway
Lipoxygenase pathway
Epoxygenase ( ___ ) pathway
Isoprostane pathway (free radical reaction)

COX
CYP450

How well did you know this?

Not at all

Perfectly

PGH synthase

both COX and ___ activities
COX reaction: radical-mediated oxidation
___ reaction: hydroperoxyl group (-OOH) to a hydroxyl group (-OH)

Hydroperoxidase

How well did you know this?

Not at all

Perfectly

Isoforms of PGH synthase

PGH synthase-1
* COX-1: housekeeping ( ___ cytoprotection)
PGH synthase 2
* COX-2: expressed upon stimulus in inflammatory and immune cells.
* Stimulated by ___ , tumor promoters, and ___ .

Inhibited by ___

gastric
growth factors, cytokines
NSAIDs

How well did you know this?

Not at all

Perfectly

Prostaglandins vs. thromboxanes

platelets = ___
vascular endothelia = ___

TXA2
PGI2

How well did you know this?

Not at all

Perfectly

Eicosanoid drugs

Alprostadil
* type: ___
* relaxes smooth muscles and ___ blood vessels
* used for ___ by injection or suppository

PGE1
expands
ED

ouch, make sure they pee before

How well did you know this?

Not at all

Perfectly

Eicosanoid drugs

Misoprostol
* ___ derivative
* Prevents ___
* when combined with ___ , terminates early pregnancy

PGE1
peptic ulcer
mifepristone

How well did you know this?

Not at all

Perfectly

Eicosanoid drugs

Latanoprost
* topically active ___ derivative (prodrug)
* ___ blood vessels
* used for glaucoma

PGF2a
constrict

How well did you know this?

Not at all

Perfectly

Eicosanoid drugs

Prostacyclin
* type: ___
* powerful ___
* inhibitor of ___
* used to treat pulmonary arterial hypertension by ___ injection or ___
* should not be used with ___

PGI2
vasodilator
platelet aggregation
IV, inhalation
anticoagulants

How well did you know this?

Not at all

Perfectly

NSAID uses

Treatment of moderate pain, ____ , and inflammation from acute
inflammation
Treatment of early-stage rheumatoid arthritis and osteoarthritis
___ prevention

fever
cancer

How well did you know this?

Not at all

Perfectly

NSAID mechanism of action

Inhibition of prostaglandin endoperoxide H synthase (PGHS or COX), which catalyzes the formation of prostaglandins.
* Many NSAIDs ___ both COX-1 and COX-2.

inhibit

How well did you know this?

Not at all

Perfectly

Classes of NSAIDs

Salicylates
Arylacetic acids
Arylpropionic acids
Non-carboxylate NSAIDs
COX-2 selective NSAIDs

How well did you know this?

Not at all

Perfectly

Example of a salicylate NSAID?

aspirin

How well did you know this?

Not at all

Perfectly

Example of aryl propionic acid NSAID?

ibuprofen

How well did you know this?

Not at all

Perfectly

Example of aryl acetic acid NSAID?

Indomethacin

How well did you know this?

Not at all

Perfectly

Example is non-carboxylate NSAID?

meloxicam

How well did you know this?

Not at all

Perfectly

Example of COX-2 Selective NSAID?

Celecoxib

How well did you know this?

Not at all

Perfectly

# Side effects of NSAIDs Gastrointestinal * mild: dyspepsia, N/V * severe: ulcer, blood loss * the ___ of NSAIDs is the primary insult * inhibition of ___ secondary insult * inhibition of ___ (increased tendency of bleeding)

* acidicty * PGEs * platelet aggregation

# Side effects of NSAIDs Blood coagulation * ____ prolongs bleeding by irreverible inhibition of platelet COX - ___ * can be used in some patients with ___ disease to prevent blood coagulation

* aspirin, 1 * cardiovascular

T or F: aspirin before surgery or tooth extraction is recommended

'FALSE; youll bleed like crazy. | contraindicated

# Side effects of NSAIDs renal * renal failure in patients with cardiovascular, ___, and ___ diseases

heptic, renal

# Side effects of NSAIDs Hypersensitivity * Characterized by skin rashes, hives, angioedema, and an asthma-like syndrome (blocked by ___ inhibitors). * Occurs in 0.3% of the population (___ % in asthmatics).

* 5-lipoxygenase * 10% | theory: higher in asthmatics due to higher baseline leukotriene levels

# Side effects of NSAIDs Reye's syndrome * specific to ___ * ___ damage common in survivors * occurs in children who have had the ___ or ___ * ___ should not be given to anyone under the age of ___ who has a ___

* salicylates * brain * flu, chicken pox * aspirin 12, fever

# Side effects of NSAIDs CNS

* tinnitus * dizziness * headache | tinnitus is ringing of the ears

# Prevention of GI side effects * misoprostol __ analog (prevents ulcers) * esomeprazole ___ inhibitor (reduced acid secretion even in the absense of COX-1 activity) * combo products: naproxen/esomeprazole, naproxen/misoprostol, diclofenac/misoprostol | Misoprostol

* PGE1 * proton pump

# Drug interactions of NSAIDs * ___ % of NSAIDs are bound to ___ * NSAIDs may ___ for serum albumin binding sites with other drugs Example – combination with oral anticoagulants * Increases the plasma concentration of free ___. * The ability of salicylate to produce GI bleeding and inhibit the clotting mechanism aggravates the problem. * Necessitates a possible ___ in the dosage of anticoagulant.

* 90-99%, albumin * compete * anticoagulant * decrease

# Structure-activity relationships in NSAIDs * commonly contains a __ group * acidic group located one carbon away from ___ or heteroaromatic ring * a methyl group on the carbon atom separating the acidic group from the aromatic ring tends to increase activity for " ___ " A second area of lipophilicity (aromatic or alkyl) that is noncoplanar with the aromatic or heteroaromatic ring generally ___ activity.

* acidic/carboxyl * "profens" * enhaces

# Salicylates * Absorbed as an ionic form from the small intestine and, to lesser extent, from the stomach as an ___ form. * Inhibits COX-1 and COX-2 ___. * May suppress COX-2 induction.

* acid * reversibly

# Salicylates - aspirin * The only NSAID that ___ inhibits COX by acetylating a ___ residue in the active site. * Absorbed largely as the intact form but hydrolyzed rapidly to salicylate by plasma ___. * Blocks platelet-aggregating factor TXA2 effectively; increases the risk of bleeding but also reduces the risk of myocardial infarction. * not ___ in solutions due to esters being sensitive to ___

* irreversibly, serine * esterase * TXA2 * stable * hydrolyzing

# Salicylates Salsalate (Disalcid®) * ___ of salicylic acid (prodrug) * hydrolyzed into 2 ___ in the small intestine and ___ * does not cause ___

* dimer * salicylates, absorbed * GI bleeding

# Salicylates Diflunisal (Dolobid®) * More ___ analgesic than aspirin, but produces ___ side effects. less ___ activity than aspirin 3-4 fold longer t1/2 than aspirin

* potent * less

# Arylacetic acids Indomethacin * one of the most ___ NSAIDs * high incidence of side effects * not suitable for ___ use * not stable in solution due to hydrolysis of ___

* potent * long term * amide bond

# Arylacetic acids Sulindac * prodrug; the ___ group is reduced to the active sulfide intermediate in the circulatory system * less ___ side effects * suitable for ___ use to treat ___ inflammation

* sulfoxide * GI * long term, chronic

# Arylacetic acids Etodolac * ___ acid * As potent as ___. * Somewhat selective for ___. * Less ___ bleeding * Suitable for ___ use to manage ___.

* Pyranocarboxylic * indomethacin * COX-2 * GI * long-term, osteoarthritis

# Arylacetic acids Diclofenac * The most widely used NSAID in the world. * As potent as ___ * Somewhat selective for ___. * Inhibits both COX and ___ pathways. * good for long term

* indomethacin * COX-2 * lipoxygenase

# Arylpropionic acids Ibuprofen (Advil® or Mortrin®) * more potent than aspirin but less than indomethacon * moderate gastric irritation * ___ group enhances it activity and reduces many side effects. Bioequivalent racemic mixture * S-(+)-enantiomer possesses ___ activity in vitro. * R-(-)-enantiomer is converted to S-(+)-enantiomer enzymatically in vivo.

* α-Methyl * greater

# Arylpropionic acids Naproxen (Aleve®) * ___ (+) - enantiomer * more potent than ibuprofen * moderate ___ * used to treat ___ arthritis and osteoarthritis

* S * gastric irritation * rheumatoid

# Arylpropionic Ketorolac * Cyclized heteroarylpropionic acid derivative * ___ management of moderate to severe pain. * Analgesic activity similar to ___ acting analgesics. * Widely accepted alternative to narcotic analgesics.

* short term * centraly (like opiates)

# Non-carboxylates Nabumetone * nonacidic prodrug * metabolized quickly to ___ which is a ___ inhibitor * minimum ___ side effects * Potent anti-inflammatory, but weak ___ activity.

* 6-MNA, COX * gastric * analgesic

# Non-carboxylates Meloxicam * Belongs to the oxicam class, which resembles the ___ intermediate in COX. * Enolic acid * ___ acting ; single daily dose. * As potent as ___. * Somewhat selective for ____. * good more longe term use

* peroxy radical intermediate * long * indomethacin * COX-2

# Consequences of COX-1 inhibition * Stomach irritation and ___ * Blockade of platelet ___ * Inhibition of uterine ___ * Inhibition of ___ mediated renal function * ___ reactions Preferential inhibition of COX-2 gives anti-inflammatory effects with lower incidence of gastric ulceration.

* ulceration * aggregation * motility * prostaglandin * hypsersensitivity

What NSAIDs are good for long term use?

* Etodolac * meloxicam * celecoxib * nimesulide

What NSAIDs are good for long term use?

* Etodolac * meloxicam * celecoxib * nimesulide

# Selective COX-2 Inhibitors * ___ in the NSAID binding site of COX-2 is substituted for ___ in that of COX-1. * Selective COX-2 inhibitors exploit the ___ NSAID binding site in COX-2 with larger and relatively rigid substituents. * "coxib"

* valine, isoleucine * larger

# Side effects of selective COX-2 inhibitors * elevated ___ and atherogenesis * expression of COX-2 in endothelium is critical for ___ production * selective COX-2 inhibitors do not affect the production of ___ by COX-1 (heightedned thrombotic response on the rupture of artherosclerotic plaque) * increased risk for heart attack and ___

* blood pressure * PGI2 (prostacyclin) * TXA2 * stroke

# Celecoxib Celebrex® * First NSAID to be marketed as selective COX-2 inhibitor. * Used for osteoarthritis and rheumatoid arthritis. * Good efficacy against pain, inflammation, and fever. * As potent as ___. * Less risk of ___ side effects. * No ___ activity.

* naproxen * GI * antiplatelet

# Acetaminophen * Analgesic and antipyretic effects similar to ___ * Much weaker as an ___ agent. * mechanism of action: Does not inhibit ___ acid binding to ___. * Scavenges ___ required for PGH synthase activity * Peroxynitrite is the major oxidant for ___ synthase activity in the ___. * In inflammation, high concentrations of ___ are present, and acetaminophen scavenging is overwhelmed.

* aspirin * anti-inflammatory * arachidonic, PGHS * peroxynitrite * PGH, CNS * peroxides

# Acetaminophen * Lower incidence of ___ and ___ * Tolerated in patients with blood ___ disorders. * Not associated with ___ syndrome. * Does not cross-react with ___ * Hepatotoxicity at toxic doses (CYP 450 mediated N-hydroxylation to form N-acetylimidoquinone which reacts with ___ ) . * Toxic doses overload the glutathione, and cell damage occurs in the liver.